Novel pharmaceutical formulation containing a biguanide and an angiotensin antagonist

ABSTRACT

A pharmaceutical dosage form comprising a controlled release component comprising an antihyperglycemic drug in combination with a second component comprising a angiotensin antagonist is herein disclosed and described.

BACKGROUND OF THE INVENTION

The present invention relates to a pharmaceutical dosage form comprisingan antihyperglycemic drug, in combination with a second drug. Morespecifically, the present invention relates to an oral dosage formcomprising a biguanide, e.g., metformin or buformin or apharmaceutically acceptable salt thereof e.g., metformin hydrochlorideor the metformin salts described in U.S. Pat. Nos. 3,957,853 and4,080,472, which are incorporated herein by reference in combinationwith an angiotensin antagonist as described in U.S. Pat. Nos. 5,196,444;5,534,534; 5,703,110; and 5,705,517 also incorporated herein byreference.

Many techniques have been used to provide controlled andextended-release pharmaceutical dosage forms in order to maintaintherapeutic serum levels of medicaments and to minimize the effects ofmissed doses of drugs caused by a lack of patient compliance.

For example, extended release tablets have been described which have anosmotically active drug core surrounded by a semi-permeable membrane.These tablets function by allowing the aqueous components of a fluidsuch as gastric or intestinal fluid to permeate the coating membrane anddissolve the active ingredient so the resultant drug solution can bereleased through a passageway in the coating membrane. Alternatively, ifthe active ingredient is insoluble in the permeating fluid, it can bepushed through the passageway by an expanding agent such as a hydrogel.Some representative examples of these osmotic tablet systems can befound in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,034,758; 4,077,407 and4,783,337. U.S. Pat. No. 3,952,741 teaches an osmotic device wherein theactive agent is released from a core surrounded by a semipermeablemembrane only after sufficient pressure has developed within themembrane to burst or rupture the membrane at a weak portion of themembrane.

The basic osmotic device described in the above cited patents have beenrefined over time in an effort to provide greater control of the releaseof the active ingredient. For example, U.S. Pat. Nos. 4,777,049 and4,851,229 describe osmotic dosage forms comprising a semipermeable wallsurrounding a core. The core contains an active ingredient and amodulating agent wherein the modulating agent causes the activeingredient to be released through a passageway in the semipermeablemembrane in a pulsed manner. Further refinements have includedmodifications to the semipermeable membrane surrounding the active coresuch as varying the proportions of the components that form themembrane, e.g. U.S. Pat. Nos. 5,178,867, 4,587,117 and 4,522,625, orincreasing the number of coatings surrounding the active core, e.g.,U.S. Pat. Nos. 5,650,170 and 4,892,739.

Certain controlled or sustained release formulations that employantihyperglycemic drugs such as metformin hydrochloride have beenlimited to the use of an expanding or gelling agent to control therelease of the drug from the dosage form. This limited research isexemplified by the teachings of WO 96/08243 and by the product insertfor GLUCOPHAGE™ XR, which is a controlled release metformin HCl productcommercially available from Bristol-Myers Squibb Co.

Angiotensin antagonists have been described in U.S. Pat. Nos. 5,196,444;5,534,534 and 5,705,517. The therapeutic value of these compounds incombination therapy has further been described in published PCTapplication WO 0215933. However, none of these patents, or thepublication describe a dosage form having the advantages of the subjectinvention.

Angiotensin antagonists are compounds functioning to control therenin-angiotensin system as well as being clinically useful for thetreatment of circulatory diseases such as hypertensive diseases, heartdiseases (e.g. hypercardia, heart failure, cardiac infarction, etc.),strokes, cerebral apoplexy, etc. These compounds are required to havepotent angiotensin II receptor antagonistic activity and to exert strongoral and long-lasting angiotensin II antagonist action. Several2-substituted benzimidazole derivatives possessing highly angiotensin IIreceptor antagonistic activity as well as exerting strong oral andlong-lasting angiotensin II antagonistic and anti-hypertensive actionhave been developed. These compounds are potent angiotensin IIantagonists that are of value in the treatment of circulatory systemdiseases such as hypertensive diseases, heart diseases, strokes,nephritis, etc.

Also known in the art is WO 99/47125 and U.S. Pat. No. 6,099,862 thatdisclose a metformin osmotic tablet coated with an immediate releasecoating containing an antihyperglycemic or a hypoglycemic drug.

Although the prior art teaches pharmaceutical dosage formulations thatcontain both an antihyperglycemic compound and an angiotensinantagonist, the present invention provides numerous benefits over theprior art teachings as will be described below.

SUMMARY OF THE INVENTION

The present invention relates to a pharmaceutical dosage form comprisinga first active drug, preferably an antihyperglycemic drug, incombination with a second active drug. The second active drug may be anydrug useful in combination therapy with the first active drug. In oneembodiment, the first active drug is a biguanide and the second activedrug is an angiotensin antagonist.

In certain embodiments, the second active drug may be selected fromantidiabetic agents, cardiovascular agents, antilipemic agents, orantiplatelet agents.

The term antidiabetic agent may include, but would not be limited tobiguanides (i.e., Metformin, Buformin, Phenformin), sulfonylureas (i.e.,Acetohexamide, Carbutamide, Chlorpropamide, Glibornuride, Gliclazide,Glimepiride, Glipizide, Gliquidone, Glisoxepid, Glyburide,Glybuthiazole, Glybuzole, Glyhexamide, Glymidine, Glypinamide,Phenbutamide, Tolazamide, Tolbutamide, Tolcyclomide) thiazolidinediones(i.e., Piogliatazone, Rosiglitazone, Troglitazone), beta andrenergicblockers, and other antidiabetics such as acarbose, calcium mesoxalate,miglitol, nateglinide, repaglinide, voglibose.

The term cardiovascular agent may include, but would not be limited to,alpha andrenergic agonists that include, but are not limited to,Adrafinil, Adrenalone, Amidephrine, Apraclonidine, Budralazine,Clonidine, Cyclopentamine, Dexmedetomidine, Dimetofrine, Dipivefrin,Ecabapide, Ephedrine, Epinephrine, Fenoxazoline, Guanabenz, Guanfacine,Hydroxyamphetamine, Ibopamine, Indanazoline, Isometheptene,Mephentermine, Metaraminol, Methoxamine, Methylhexaneamine, Midodrine,Mivazerol, Modafinil, Moxonidine, Naphazoline, Norepinephrine,Norfenefrine, Octodrine, Octopamine, Oxymetazoline, PhenylephrineHydrochloride, Phenylpropanolamine, Phenylpropylmethylamine, Pholedrine,Propylhexedrine, Pseudoephedrine, Rilmenidine, Synephrine, Talipexole,Tetrahydrozoline, Tiamenidine, Tramazoline, Tuaminoheptane, Tymazoline,Tyramine, and Xylometazoline.

Beta andrenergic agonists include but are not limited to Albuterol,Bambuterol, Bitolterol, Carbuterol, Clenbuterol, Clorprenaline,Denopamine, Dixoethedrine, Dopexamine, Ephedrine, Epinephrine,Etafedrine, Ethylnorepinephrine, Fenoterol, Formoterol, Hexoprenaline,Ibopamine, Isoetharine, Isoproterenol, Methoxyphenamine, Mabuterol,Metaproterenol, Oxyfedrine, Pirbuterol, Prenalterol, Procaterol,Protokylol, Reproterol, Rimiterol, Ritodrine, Salmeterol, Soterenol,Terbutaline, Tretoquinol, Tulobuterol, and Xamoterol.

Alpha andrenergic blockers include but are not limited to Amosulalol,Arotinolol, Dapiprazole, Doxazosin, Ergoloid Mesylates, Fenspiride,Idazoxan, Indoramin, Labetalol, Monatepil, Naftopidil, Nicergoline,Prazosin, Tamsulosin, Terazosin, Tolazoline, Trimazosin and Yohimbine.

Beta andrenergic blockers include but are not limited to Acebutolol,Alprenolol, Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol,Bevantolol, Bisoprolol, Bopindolol, Bucindolol, Bucumolol, Bufetolol,Bufuralol, Bunitrolol, Bupranolol, Butidrine Hydrochloride, Butofilol,Carazolol, Carteolol, Carvedilol, Celiprolol, Cetamolol, Cloranolol,Dilevalol, Esmolol, Indenolol, Labetalol, Landiolol, Levobunolol,Mepindolol, Metipranolol, Metoprolol, Moprolol, Nadolol, Nadoxolol,Nebivolol, Nifenalol, Nipradilol, Oxprenolol, Penbutolol, Pindolol,Practolol, Pronethalol, Propanolol, Sotalol, Sulfinalol, Talinolol,Tertatolol, Tilisolol, Timolol, Toliprolol and Xibenolol.

Antiarrhythmics include but are not limited to Acebutolol, Acecainide,Adenosine, Ajmaline, Alprenolol, Amiodarone, Aprindine, Arotinolol,Atenolol, Azimilide, Bevantolol, Bidisomide, Bretylium Tosylate,Bucumolol, Bufetolol, Bunaftine, Bunitrolol, Bupranolol, ButidrineHydrochloride, Butobendine, Capobenic Acid, Carazolol, Carteolol,Cifenline, Cloranolol, Disopyramide, Dofetilide, Encainide, Esmolol,Flecainide, Hydroquinidine, Ibutilide, Indecainide, Indenolol,Ipratropium Bromide, Landiolol, Lidocaine, Lorajmine, Lorcainide,Meobentine, Mexiletine, Moricizine, Nadoxolol, Nifenalol, Oxprenolol,Penbutolol, Pentisomide, Pilsicainide, Pindolol, Pirmenol, Practolol,Prajmaline, Procainamide Hydrochloride, Pronethalol, Propafenone,Propranolol, Pyrinoline, Quinidine, Sematilide, Sotalol, Talinolol,Tedisamil, Tilisolol, Timolol, Tocainide, Verapamil and Xibenolol.

Calcium channel blockers include but are not limited to Arylalkylamines:Bepridil, Clentiazem, Diltiazem, Fendiline, Gallopamil, Mibefradil,Prenylamine, Semotiadil, Terodiline, Verapamil; DihydropyridineDerivatives: Amlodipine, Aranidipine, Bamidipine, Benidipine,Cilnidipine, Efonidipine, Elgodipine, Felodipine, Isradipine,Lacidipine, Lercanidipine, Manidipine, Nicardipine, Nifedipine,Nilvadipine, Nimodipine, Nisoldipine, Nitrendipine; PiperazineDerivatives: Cinnarizine, Dotarizine, Flunarizine, Lidoflazine,Lomerizine; and others: Bencyclane, Etafenone, Fantofarone, Monatepil,and Perhexiline.

Inotropic agents include but are not limited to Digoxin, Milrinone,Dobutamine, and Dopamine.

Vasodilators include but are not limited to Amotriphene, BenfurodilHemisuccinate, Benziodarone, Chloracizine, Chromonar, Clobenfurol,Clonitrate, Cloricromen, Dilazep, Droprenilamine, Efloxate, ErythritylTetranitrate, Etafenone, Fendiline, Hexestrol Bis (β-diethylaminoethyl)ether, Hexobendine, Itramin Tosylate, Khellin, Lidoflazine, MannitolHexanitrate, Nitroglycerin, Pentaerythritol Tetranitrate, Pentrinitrol,Perhexiline, Pimefylline, Prenylamine, Propatyl Nitrate, Trapidil,Tricromyl, Trimetazidine, Trolnitrate Phosphate and Visnadine.

Vasopressors include but are not limited to Antihypotensive: AmeziniumMethyl Sulfate, Angiotensin Amide, Dopamine, Dimetofrine, Etifelmin,Etilefrin, Gepefrine, Metaraminol, Methoxamine, Midodrine,Norepinephrine, Pholedrine and Synephrine.

The term antiplipemic agents may include, but would not be limited tobile acid sequesterants, fibric acid derivatives, HMG CoA reductaseinhibitors, and nicotinic acid.

Bile Acid Sequesterants include but are not limited to CholestyramineResin, Cholesevelam Hydrochloride, Colestipol, and Polidexide.

Fibric Acid Derivatives include but are not limited to Bezafibrate,Binifibrate, Ciprofibrate, Clinofibrate, Clofibrate, Clofibric Acid,Etofibrate, Fenofibrate, Gemfibrozil, Pirifibrate, Ronifibrate,Simfibrate and Theofibrate.

HMG CoA Reductase inhibitors include but are not limited toAtorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pravastatin Sodiumand Simvastatin.

Nicotidine Acid Derivatives include but are not limited to Acipimox,Aluminum Nicotinate, Niceritrol, Nicoclonate, Nicomol, and OxiniacicAcid.

Other Antilipemic agents include but are not limited to Acifran,Benfluorex, β-Benzalbutyramide, Carnitine, Chonodroitin Sulfate,Clomestrone, Detaxtran, Dextran Sulfate Sodium, Eicosapentaenoic Acid,Eritadenine, Ezetimibe, Furazabol, Meglutol, Melinamide, γ-Oryzanol,Pantethine, Pentaerythritol Tetraacetate, α-Phenylbutyramide, Pirozadil,Probucol, β-Sitosterol, Sultosilic Acid, Tiadenol, Triparanol, andXenbucin.

The term antiplatelet agents may include, but would not be limited toTirofiban, Dipyridamole, Anagrelide, Epoprostanol, Eptifibatide,Clopidrogel, Cilostazole and Triclopidine.

The foregoing objectives are met by a dosage form comprising a first andsecond active drug, wherein the first active drug is formulated as acontrolled release core, preferably an osmotic tablet, with or without agelling or expanding polymer. The second active ingredient may be partof the controlled release core or it may be combined with the controlledrelease core in a manner that provides for immediate release of thesecond active ingredient. For example, the second active ingredient canbe incorporated into a membrane that is applied to the core or thesecond active ingredient may be applied to a coated or uncoatedcontrolled release core.

In some embodiments, the dosage form may also comprise a capsulecontaining a controlled release tablet of the first drug and animmediate release tablet of the second drug, a controlled release tabletof the first drug and a controlled release tablet of the second drug, acontrolled release tablet of the first drug and an immediate releaseparticles of the second drug, a controlled release tablet of the firstdrug and a controlled release particles of the second drug, a controlledrelease tablet of the first drug and immediate release granules of thesecond drug, a controlled release tablet of the first drug andcontrolled release granules of the second drug, a controlled releasetablet of the first drug and immediate release pellets of the seconddrug, a controlled release tablet of the first drug and controlledrelease pellets of the second drug.

In one embodiment the second active drug, which may be an angiotensinantagonist is provided as an immediate release formulation in the dosageform whereas the antihyperglycemic component is provided as a controlledrelease formulation in the dosage form. This immediate release portionof the formulation should provide peak plasma levels (T_(max)) of up toabout 24 hours preferably up to about 12 hours, and further preferred upto about 8 hours, while the controlled release portion of theformulation may provide peak plasma levels (T_(max)) of up to about 24hours preferably up to about 12 hours, and further preferred up to about8 hours of the antihyperglycemic component.

Preferably, the dosage form according to the subject invention may beadministered once a day, preferably with or after a meal, and mostpreferably with or after the evening meal. The subject dosage form canprovide therapeutic levels of the drug throughout the day with peakplasma levels (T_(max)) of the antihyperglycemic drug being obtainedbetween and up to about 24 hours after administration.

It is an object of the present invention to provide a dosage formcomprising a first active drug, which is formulated to provide acontrolled or sustained release delivery. Preferably, the first activedrug is an antihyperglycemic compound. The present invention furtherprovides for a second active drug, which preferably is an angiotensinantagonist. The novel dosage form described herein provides for deliveryof first and second active drugs such that the bioavailability of eitherdrug is not decreased by the presence of food.

It is a further object of the present invention to provide a dosageform, as described above, comprising delivery of a first active drug asa controlled or sustained release formulation for an antihyperglycemiccompound, wherein said controlled or sustained release mechanism is notregulated by an expanding polymer, in combination with delivery of asecond active drug by immediate release comprising an angiotensinantagonist.

It is a further object of the present invention to provide a dosageform, as described above, comprising delivery of a first active drug asa controlled or sustained release formulation for an antihyperglycemiccompound, wherein said controlled or sustained release mechanism is notregulated by an expanding polymer, in combination with delivery of asecond active drug by controlled release comprising an angiotensinantagonist.

It is also a further object of the present invention to provide a dosageform as described above, comprising delivery of a first active drug as acontrolled or sustained release formulation for an antihyperglycemiccompound in combination with delivery of a second active drug byimmediate release comprising an angiotensin antagonist that can providecontinuous and non-pulsating therapeutic levels of saidantihyperglycemic drug to an animal or human in need of such treatmentup to a twenty-four hour period. In certain embodiments the subjectinvention provides therapeutic levels over an eight hour to twenty-fourhour period.

It is an additional object of the present invention to provide a dosageform comprising delivery of a first active drug as a controlled orsustained release formulation for an antihyperglycemic compound incombination with delivery of a second active drug by immediate releasecomprising an angiotensin antagonist that obtains peak plasma levels ofthe antihyperglycemic compound up to approximately 24 hours. In certainembodiments, the approximately peak plasma levels of theantihyperglycemic compound occur in up to about 12 hours. In yet anotherembodiment peak, plasma levels of the antihyperglycemic compound occurin approximately 1-12 hours after administration. In certainembodiments, the peak plasma levels of an angiotensin antagonist occurin approximately up to 8 hours after dosing. In certain embodiments, thepeak plasma levels of an angiotensin antagonist occur in approximatelyup to 6 hours after dosing. In certain embodiments, the peak plasmalevels of an angiotensin antagonist occur in approximately up to 4 hoursafter dosing. In certain embodiments, the peak plasma levels of anangiotensin antagonist occur in approximately 1-4 hours after dosing.

It is an additional object of the present invention to provide a dosageform comprising delivery of a first active drug as a controlled orsustained release formulation for an antihyperglycemic compound incombination with delivery of a second active drug by controlled releasecomprising an angiotensin antagonist that obtains peak plasma levels ofthe angiotensin antagonist that obtains peak plasma levels of theantihyperglycemic compound up to approximately 24 hours. In certainembodiments the approximately peak plasma levels of theantihyperglycemic compound occur in up to about 12 hours. In yet anotherembodiment, peak plasma levels of the antihyperglycemic compound occurin approximately 1-12 hours after administration. In certainembodiments, the peak plasma levels of an angiotensin antagonist occurin approximately up to 8 hours after dosing. In certain embodiments, thepeak plasma levels of an angiotensin antagonist occur in approximatelyup to 6 hours after dosing. In certain embodiments, the peak plasmalevels of an angiotensin antagonist occur in approximately up to 4 hoursafter dosing. In certain embodiments, the peak plasma levels of anangiotensin antagonist occur in approximately 1-4 hours after dosing.

It is also an object of the present invention to provide a dosage formcomprising a first active drug as a controlled or sustained releasepharmaceutical core tablet having only a homogeneous osmotic corewherein the osmotic core component may be made using ordinary tabletcompression techniques.

It is a further object of the present invention to provide a dosage formcomprising an antihyperglycemic drug as a controlled or sustainedrelease component and an angiotensin antagonist as an immediate releasecomponent, wherein not less than 85% of the total amount of theangiotensin antagonist is released from the dosage form within 60minutes or less.

The foregoing objectives are met by a dosage form comprising a first andsecond active drug, wherein the first active drug is formulated as acontrolled release core, preferably an osmotic tablet, with or without agelling or expanding polymer.

The second active ingredient may be part of the controlled release coreor it may preferably be combined with the controlled release core in amanner that provides for immediate release of the second activeingredient. For example, the second active ingredient can beincorporated into a membrane that is applied to the core or the secondactive ingredient may be applied to a coated or uncoated controlledrelease core.

DETAILED DESCRIPTION OF THE INVENTION

The subject invention concerns a pharmaceutical formulation or dosageform comprising a first active drug comprising an antihyperglycemic drugin combination with a second active drug comprising an angiotensinantagonist. Preferably, the antihyperglycemic drug is a biguanide, e.g.,metformin or buformin or a pharmaceutically acceptable salt thereof. Theantihyperglycemic drug is delivered in a controlled release manner froma tablet core. In one embodiment, controlled release of theantihyperglycemic drugs occurs from an osmotic tablet core with orwithout a gelling or swelling polymer. The tablet core should includethe antihyperglycemic drug and at least one pharmaceutically acceptableexcipient. In one embodiment of the present invention the tablet coreincludes the antihyperglycemic drug, a binding agent and an absorptionenhancer, and the tablet core is preferably coated with a polymericcoating to form a membrane around the tablet and drilled to create onepassageway through the membrane on each side of the tablet. The secondactive drug comprises an angiotensin antagonist, and is preferablyapplied to the membrane of the tablet core and provides for eitherimmediate or controlled release of said angiotensin antagonist.

The term, antihyperglycemic drugs as used in this specification, refersto drugs that are useful in controlling or managing noninsulin-dependentdiabetes mellitus (NIDDM). Antihyperglycemic drugs include thebiguanides such as metformin, phenformin or buformin or the like, andpharmaceutically acceptable salts, isomers or derivatives thereof.

The term angiotensin antagonist as used in this specification refers todrugs that are useful for controlling or managing NIDDM. These include,but are not limited to, valsartan, losartan, candesartan, eprosartan,irbesartan, olmesartan, tasosartan, and telmisartan or the like, andpharmaceutically acceptable salts, isomers or derivatives thereof.

The term controlled release refers to the spectrum of deliverytechniques in pharmaceutical formulations. These may include, but wouldnot be limited to, sustained release, delayed release, targeteddelivery, modified release, rapid release, or any other technique inwhich the dosage form affects the release of the drug.

The term binding agent refers to any conventionally knownpharmaceutically acceptable binder such as polyvinyl pyrrolidone,hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, ethylcellulose, polymethacrylate, polyvinylalcohol,waxes and the like. Mixtures of the aforementioned binding agents mayalso be used. The preferred binding agents are water soluble materialssuch as polyvinyl pyrrolidone having a weight average molecular weightof 25,000 to 3,000,000. The binding agent may comprise approximatelyabout 0 to about 40% of the total weight of the core and preferablyabout 3% to about 15% of the total weight of the core. In oneembodiment, the use of a binding agent in the core is optional.

In a preferred embodiment, the core may optionally comprise anabsorption enhancer. The absorption enhancer can be any type ofabsorption enhancer commonly known in the art such as a fatty acid, asurfactant, a chelating agent, a bile salt or mixtures thereof. Examplesof some preferred absorption enhancers are fatty acids such as capricacid, oleic acid and their monoglycerides, surfactants such as sodiumlauiyl sulfate, sodium taurocholate and polysorbate 80, chelating agentssuch as citric acid, phytic acid, ethylenediamine tetraacetic acid(EDTA) and ethylene glycol-bis(β-aminoethyl ether)-N,N,N,N-tetraaceticacid (EGTA). The core may comprise approximately 0 to about 20% of theabsorption enhancer based on the total weight of the core and the mostpreferably about 2% to about 10% of the total weight of the core.

In one embodiment of the present invention, which does not employ agelling or swelling polymer, the core of the present invention ispreferably formed by granulating an antihyperglycemic drug with abinding agent and compressing the granules with the addition of alubricant and absorption enhancer into a tablet. The core may also beformed by dry granulating the core ingredients by passing them through aroller compactor and compressing the granules with the addition of alubricant into tablets. Direct compression may also be employed fortabletting. The tablets may be manufactured by other commonly knowngranulation procedures that are known in the art. Additionally, otherexcipients such as lubricants, pigments or dyes may also be employed inthe formulation of the subject invention.

The term gelling or swelling polymer refers to polymers that gel, swellor expand in the presence of water or biological fluids. Representativeexamples of gelling or swelling polymers are high molecular weighthydroxpropyl methylcellulose (such as METHOCEL® K100M, which iscommercially available from Dow Chemical) and high molecular weightpolyethylene oxides (such as POLYOX WSR 301, WSR 303 or WSR COAGULANT).Other gelling or swelling polymers are described in U.S. Pat. No.4,522,625 (which is incorporated herein by reference).

The core formed as described herein, can be coated with a membrane orsustained release coating. Materials that are useful in forming themembrane or sustained release coating are ethylcellulose, celluloseesters, cellulose diesters, cellulose triesters, cellulose ethers,cellulose ester-ether, cellulose acylate, cellulose diacylate, cellulosetriacylate, cellulose acetate, cellulose diacetate, cellulosetriacetate, cellulose acetate propionate and cellulose acetate butyrate.Other suitable polymers are described in U.S. Pat. Nos. 3,845,770;3,916,899; 4,008,719; 4,036,228 and 4,612,008 (which are incorporatedherein by reference). The most preferred membrane or sustained releasecoating material is cellulose acetate comprising an acetyl content of39.3 to 40.3%, and is commercially available from Eastman FineChemicals.

In an alternative embodiment, the membrane or sustained release coatingcan include one of the above-described polymers and a flux-enhancingagent. The flux enhancing agent can increase the volume of fluid imbibedinto the core to enable the dosage form to dispense substantially all ofthe antihyperglycemic drug through the passageway and/or the porousmembrane. The flux-enhancing agent can be a water-soluble material or anenteric material. Examples of the preferred materials that are useful asflux enhancers are sodium chloride, potassium chloride, sucrose,sorbitol, mannitol, polyethylene glycol (PEG), propylene glycol,hydroxypropyl cellulose, hydroxypropyl methycellulose, hydroxypropylmethycellulose phthalate, cellulose acetate phthalate, polyvinylalcohols, methacrylic acid copolymers, poloxamers (such as LUTROL F68,LUTROL F127, LUTROL F108, which are commercially available from BASF)and mixtures thereof A preferred flux-enhancer is PEG 400.

The flux enhancer may also be a drug that is water soluble such asmetformin or its pharmaceutically acceptable salts, or the flux enhancermay be a drug that is soluble under intestinal conditions. If the fluxenhancer is a drug, the present dosage form has the added advantage ofproviding an immediate release of the drug that has been selected as theflux enhancer.

The flux enhancing agent comprises approximately 0 to about 40% of thetotal weight of the coating, most preferably about 2% to about 20% ofthe total weight of the coating. The flux enhancing agent dissolves orleaches from the membrane or sustained release coating to form paths inthe membrane or sustained release coating, which enables fluid to enterthe core and dissolve the active ingredient.

The membrane or sustained release coating may also be formed using acommonly known excipient such as a plasticizer. Some commonly knownplasticizers include adipate, azelate, enzoate, citrate, stearate,isoebucate, sebacate, triethyl citrate, tri-n-butyl citrate, acetyltri-n-butyl citrate, citric acid esters, and those described in theEncyclopedia of Polymer Science and Technology, Vol. 10 (1969),published by John Wiley & Sons. The preferred plasticizers aretriacetin, acetylated monoglyceride, grape seed oil, olive oil, sesameoil, acetyltributylcitrate, acetyltriethylcitrate, glycerin sorbitol,diethyloxalate, diethylmalate, diethylfumarate, dibutylsuccinate,diethylmalonate, dioctylphthalate, dibutylsebacate, triethylcitrate,tributylcitrate, glyceroltributyrate and the like. Depending on theparticular plasticizer, amounts from about 0 to about 25%, andpreferably about 2% to about 15% of the plasticizer can be used basedupon the total weight of the membrane or sustained release coating.

Generally, the membrane or sustained release coating around the corewill comprise from about 1% to about 5% and preferably about 2% to about3% based upon the total weight of the core and coating.

In a preferred embodiment, the membrane or sustained release coatingsurrounding the core further comprises a passageway that will allow forcontrolled release of the drug from the core. As used herein the termpassageway includes an aperture, orifice, bore, hole, weakened area oran erodible element such as a gelatin plug that erodes to form anosmotic passageway for the release of the antihyperglycemic drug fromthe dosage form. Passageways used in accordance with the subjectinvention are well known and are described in U.S. Pat. Nos. 3,845,770;3,916,899; 4,034,758; 4,077,407; 4,783,337 and 5,071,607.

Independent of the antihyperglycemic is a second active drug. In oneembodiment the preferred second drug is an angiotensin antagonist. Thissecond active drug may be formulated to provide an immediate release ofthe angiotensin antagonist. In one embodiment of the present inventionthe angiotensin antagonist is applied in the form of a layer to acontrolled or sustained released core comprising the antihyperglycemicdrug as a layer using a binder and other conventional pharmaceuticalexcipients such as absorption enhancers, surfactants, plasticizers,antifoaming agents and combinations of the foregoing. An absorptionenhancer may be present in the angiotensin antagonist layer in an amountup to about 30% w/w in comparison to the weight of the angiotensinantagonist. A binding agent may be present in an amount up to 150% w/wof the angiotensin antagonist. A second active drug immediate releaseformulation may be incorporated into a single dosage form by coatingonto the membrane or sustained release coating of the dosage form byconventional methods. Alternatively, it may be incorporated by anypharmaceutically acceptable method into a single dosage form with thefirst active drug. The incorporation of the second active drug may beperformed by, but would not be limited to, the processes selected fromthe group consisting of drug layering, coating, lamination, drycompression, deposition and printing.

When the angiotensin antagonist is coated onto a membrane or sustainedrelease coating of an osmotic tablet core, the angiotensin antagonistshould be applied from a coating solution or suspension that employs anaqueous solvent, an organic solvent or a mixture of an aqueous and anorganic solvent. Typical organic solvents include acetone, isopropylalcohol, methanol and ethanol. If a mixture of aqueous and organicsolvents is employed, the ratio of water to organic solvent should rangefrom 98:2 to 2:98, preferably 50:50 to 2:98. If a mixed solvent systemis employed, the amount of binder required for coating the angiotensinantagonist onto the membrane or sustained release coating may bereduced. For example, successful coatings have been obtained from amixed solvent system where the ratio of binder to angiotensin antagonistis 1:9 to 1:11. Although acceptable coatings can be obtained when theangiotensin antagonist coat is applied directly to the membrane orsustained release coating, a preferred approach is to first coat themembrane or sustained release coating with a seal coat prior to theapplication of the angiotensin antagonist coating. As used herein a sealcoat is a coating that does not contain an active pharmaceuticalingredient and that rapidly disperses or dissolves in water.

The angiotensin antagonist coating solution or suspension may alsocontain a surfactant and a pore forming agent. A pore forming agent ispreferably a water-soluble material such as sodium chloride, potassiumchloride, sucrose, sorbitol, mannitol, polyethylene glycol (PEG),propylene glycol, hydroxypropyl cellulose, hydroxypropyl methycellulose,hydroxypropyl methycellulose phthalate, cellulose acetate phthalate,polyvinyl alcohols, methacrylic acid copolymers, poloxamers (such asLUTROL F68, LUTROL F127, LUTROL F108, which are commercially availablefrom BASF) and mixtures thereof. In an alternative embodiment, thedosage form of the present invention may also comprise an effectiveimmediate release amount of the antihyperglycemic drug. The effectiveimmediate release amount of antihyperglycemic drug may be coated ontothe membrane or sustained release coating of the dosage form or it maybe incorporated into the membrane or sustained release coating.

In addition, various diluents, excipients, lubricants, dyes, pigments,dispersants, etc., which are disclosed in Remington's PharmaceuticalSciences (1995), may be used to optimize the above listed formulationsof the subject invention.

Biguanides, such as metformin are commonly administered in dosage formscontaining 500 mg, 750 mg, 850 mg, and 1000 mg. Angiotensin antagonists,for example candesartan, are commonly administered in dosage formscontaining 4 mg, 8 mg, 16 mg and 32 mg. The present invention isintended to encompass the above listed therapeutic combinations, withoutproviding a specific example of each possible combination of compoundsand their respective dosage amounts.

A preferred embodiment the dosage form will have the followingcomposition:

FIRST ACTIVE DRUG Core: Amount (% of core) drug 50-98% (75-95%preferred)  binder 0.1-40%  (3-15% preferred) absorption enhancer  0-20%(2-10% preferred) lubricant  0-5% (0.5-1% preferred)  Coating: Amount (%of coating) polymer 50-99%  (75-95% preferred)  flux enhancer 0-40%(2-20% preferred) plasticizer 0-25% (2-15% preferred) SECOND ACTIVE DRUGAmount (% of total dosage form) drug 0.1-20%   (1-10% preferred) binder0.1-30%   (1-15% preferred) surfactant 0-20% (0.1-15% preferred) poreformer 0-25% (0.1-15% preferred) polymer (optional) 0-30% (0.1-20%preferred)

The dosage forms prepared according to the present invention exhibit thefollowing dissolution profile when tested in a USP Apparatus 2 apparatusat 75 rpm in 900 mL of simulated intestinal fluid (pH 7.5 phosphatebuffer) and at 37° C.:

Time (hours) % release Release of First Active Drug 2   0-25% (0-15%preferred) 4   10-45% (20-40% preferred) 8   30-90% (45-90% preferred)12 NLT 50% (NLT 60% preferred) 16 NLT 60% (NLT 70% preferred) 20 NLT 70%(NLT 80% preferred) Release of Second Active Drug 0.5 NLT 60% (NLT 75%preferred) NLT = NOT LESS THAN

It has been discovered that the selection of the excipients for use inthe angiotensin antagonist component of the dosage form can greatlyaffect the release characteristics, potency and stability of theangiotensin antagonist. Therefore, in an alternate embodiment of thepresent invention, the composition of the angiotensin antagonistcomponent of the present invention should be selected so that not lessthan 85%, preferably not less than 90% and most preferably not less than95% of the angiotensin antagonist is released from the dosage fonnwithin 45 minutes, preferably within 40 minutes and most preferablywithin 30 minutes when tested according to the United StatesPharmacopeia (USP) 26, with Apparatus 1 at 100 rpm, 37° C. and 900 mL of0.3 M KCl-HCl Buffer, pH 2.0.

A preferred embodiment of the present invention will exhibitpharmacokinetic parameters for the antihyperglycemic drug that aresimilar to the pharmacokinetic parameters described in Published UnitedStates Patent Application Nos. 200100224659; 20040052848; and20040219209 which are incorporated herein by reference. Morespecifically an embodiment of the present invention should exhibit aC_(max) of about 45-80%, prefereably about 50-75%, of the C_(max) of anequivalent dose of an immediate release antihyperglycemic drug and aT_(max) of about 160 to about 225%, preferably about 170 to about 215,of the T_(max) of an equivalent does of an immediate release ofantihyperglycemic drug. Further, an embodiment of the present inventionwould provide a C_(max) for the antihyperglycemic drug of about1500ng/mL to about 3000 ng/mL, based upon administration of a 2000 gmonce-a-day dose of antihyperglycemic drug, more preferably about 1700ng/mL to about 2000 ng/mL based upon administration of a 2000 gmonce-a-day dose of antihyperglycemic drug. Still further, an embodimentof the present invention would provide a mean AUC₀₋₂₄ for theantihyperglycemic drug of about 17200 ng·hr/mL to about 33900 ng·hr/mL,based upon administration of a 2000 gm once-a-day dose ofantihyperglycemic drug, preferably about 17200 ng·hr/mL to about 26500ng·hr/mL based upon administration of a 2000 gm once-a-day dose ofantihyperglycemic drug.

EXAMPLES

The following are provided by way of example only and are in no meansintended to be limiting.

Example 1

A controlled release tablet containing 850 mg of metformin HCl and 16 mgcandesartan celexitil is prepared as follows:

First Active Drug I. Core (% composition of core) Metformin HCl 90.54%Povidone K-30¹, USP 4.38% Sodium Tribasic Phosphate 4.58% Magnesiumstearate 0.5% ¹approximate molecular weight = 50,000; dynamic viscosity(10% w/v solution at 20° C.) = 5.5-8.5 m Pa s.

(a) Granulation

The metformin HCl is delumped by passing it through a 40 mesh screen andcollecting it in a clean, polyethylene-lined container. The povidone(K-30) and sodium tribasic phosphate are dissolved in purified water.The delumped metformin HCl is then added to a top-spray fluidized bedgranulator and granulated by spraying the binding solution of povidoneand sodium tribasic phosphate under the following conditions: inlet airtemperature of 50-70° C.; atomization air pressure of 1-3 bars and sprayrate of 10-100 mL/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss on drying is less than 2%. The dried granulesare passed through a Comil equipped with the equivalent of an 18 meshscreen.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the granules are compressed on arotary press fitted with 15/32″ round standard concave punches (plainlower punch, upper punch with an approximately 1 mm indentation pin).

As stated above, the orifice may be formed by any means commonlyemployed in the pharmaceutical industry.

(c) Seal Coating (Optional)

The core tablet can be seal coated with an Opadry material or othersuitable water-soluble material by first dissolving the Opadry material,preferably Opadry Clear, in purified water. The Opadry solution is thensprayed onto the core tablet using a pan coater under the followingconditions: exhaust air temperature of 38-42° C.; atomization pressureof 28-40 psi and spay rate of 10-15 mL/min. The core tablet is coatedwith the sealing solution until a theoretical coating level ofapproximately 1-2% is obtained.

II Membrane (% composition of membrane) Cellulose Acetate (398-10)² 85%Triacetin  5% PEG 400 10% ²acetyl content 39.3-40.3%

(a) Membrane Coating Process

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred until a clear solution isobtained. The clear coating solution is then sprayed onto the sealcoated tablets in a fluidized bed coater employing the followingconditions: product temperature of 16-22° C.; atomization pressure ofapproximately 3 bars and spray rate of 120-150 mL/min. The sealed coretablet is coated until a theoretical coating level of approximately 3%is obtained.

(% composition of III. Second Active Drug Layering second component)Canadesartan Cilexetil 43.5% Tween 80% 2.0% Hydroxypropylmethylcellulose 54.5%

Tween 80 and hydroxpropyl methylcellulose are dissolved in purifiedwater. Canadesartan Cilexetil is then dispersed into this solution. Theresulting suspension is then sprayed onto the above-described tablets.

Example 2

A controlled release tablet containing 850 mg of metformin HCl and 16 mgCandesartan Cilexetil is prepared as follows:

First Active Drug I. Core (% composition of core) Metformin HCl 88.555%Povidone K-90³, USP 6.368% Sodium Lauryl Sulfate 4.577% MagnesiumStearate 0.5% ³approximate molecular weight = 1,000,000 dynamicviscosity (10% w/v solution at 20° C. = 300-700 m Pa s.

(a) Granulation

The metformin HCl and sodium lauryl sulfate are delumped by passing themthrough a 40 mesh screen and collecting them in a clean,polyethylene-lined container. The povidone (K-90) is dissolved inpurified water. The delumped metformin HCl and sodium lauryl sulfate arethen added to a top-spray fluidized bed granulator and granulated byspraying with the binding solution of povidone under the followingconditions: inlet air temperature of 50-70° C., atomization air pressureof 1-3 bars and spray rate of 10-100 mL/min.

Once the binding solution is depleted, the granules are dried in thegranulator until the loss of drying is less than 2%. The dried granulesare passed through a comil equipped with the equivalent of an 18 meshscreen.

(b) Tableting

The magnesium stearate is passed through a 40 mesh stainless steelscreen and blended with the metformin HCl granules for approximatelyfive (5) minutes. After blending, the granules are compressed on arotary press fitted with 15/32″ round standard concave punches (plainlower punch, upper punch with an approximately 1 mm indentation pin).

As stated above, the orifice may be formed by any means commonlyemployed in the pharmaceutical industry.

(c) Seal Coating (Optional)

The core tablet is seal coated with an Opadry material or other suitablewater-soluble material by first dissolving the Opadry material,preferably Opadry Clear, in purified water. The Opadry solution is thensprayed onto the core tablet using a pan coater under the followingconditions: exhaust air temperature of 38-42° C.; atomization pressureof 28-40 psi and spay rate of 10-15 mL/min. The core tablet is coatedwith the sealing solution until a theoretical coating level ofapproximately 2% is obtained.

II Membrane (% composition of membrane) Cellulose Acetate (398-10)⁴ 85%Triacetin  5% PEG 400 10% ⁴acetyl content 39.3-40.3%

(a) Membrane Coating Process

The cellulose acetate is dissolved in acetone while stirring with ahomogenizer. The polyethylene glycol 400 and triacetin are added to thecellulose acetate solution and stirred until a clear solution isobtained. The clear coating solution is then sprayed onto the sealcoated tablets in a fluidized bed coater employing the followingconditions: product temperature of 16-22° C.; atomization pressure ofapproximately 3 bars and spray rate of 120-150 mL/min. The sealed coretablet is coated until a theoretical coating level of approximately 3%is obtained.

(% composition of III. Second Active Drug Layering second component)Candesartan Cilexetil 43.5% Tween 80 2.0% Hydroxypropyl methylcellulose54.5%

Tween 80 and hydroxypropyl methylcellulose are dissolved in purifiedwater. Candesartan Cilexetil is then dispersed into this solution. Theresulting suspension is then sprayed onto the above-described tablets.

While certain preferred and alternative embodiments of the inventionhave been set forth for purposes of disclosing the invention,modifications to the disclosed embodiments may occur to those who areskilled in the art. Accordingly, the appended claims are intended tocover all embodiments of the invention and modifications thereof whichdo not depart from the spirit and scope of the invention.

1-49. (canceled)
 50. A method for treating patients with circulatory system diseases, noninsulin-dependent diabetes mellitus or combinations of the forgoing comprising orally administering once-a-day to the patient a solid pharmaceutical dosage form comprising: (a) an antihyperglycemic drug which is metformin or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable controlled release excipient; and (b) an angiotensin antagonist selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan, tasosartan, and telmisartan, and pharmaceutically acceptable salts, isomers or derivatives thereof; and wherein said dosage form exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 mL of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37° C.: after 0.5 hours not less than 75% of the angiotensin antagonist is released; after 2 hours 0-25% of the antihyperglycemic drug is released; after 4 hours 10-45% of the antihyperglycemic drug is released; after 8 hours 30-90% of the antihyperglycemic drug is released; after 12 hours not less than 50% of the antihyperglycemic drug is released; after 16 hours not less than 60% of the antihyperglycemic drug is released; and after 20 hours not less than 70% of the antihyperglycemic drug is released.
 51. The method of claim 50, wherein said angiotensin antagonist is candesartan.
 52. The method of claim 50, wherein said dosage form is substantially free from any gelling or expanding polymer.
 53. The method of claim 50 wherein said release of said antihyperglycemic drug provides a T_(max) of 8-12 hours.
 54. The method of claim 50 wherein said release of the angiotensin antagonist provides a T_(max) of 1-12 hours.
 55. The method of claim 50 wherein said release of the angiotensin antagonist provides a T_(max) of 1-4 hours.
 56. The method of claim 50, wherein said dosage form exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 mL of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37° C.: after 2 hours 0-15% of the antihyperglycemic drug is released; after 4 hours 20-40% of the antihyperglycemic drug is released; after 8 hours 45-90% of the antihyperglycemic drug is released; after 12 hours not less than 60% of the antihyperglycemic drug is released; after 16 hours not less than 70% of the antihyperglycemic drug is released; and after 20 hours not less than 80% of the antihyperglycemic drug is released.
 57. The method of claim 50, wherein said dosage form exhibits the following dissolution profile when tested in a USP type 1 apparatus at 100 rpm in 900 mL of 0.3 M KCl-HCl buffer, pH 2.0 and at 37° C.: after 45 minutes not less than 85% of the angiotensin antagonist drug is released.
 58. The method of claim 50, wherein said dosage form exhibits the following dissolution profile when tested in a USP type 1 apparatus at 100 rpm in 900 mL of 0.3 M KCl-HCl buffer, pH 2.0 and at 37° C.: after 45 minutes not less than 90% of the angiotensin antagonist drug is released.
 59. The method of claim 50, wherein said dosage form exhibits the following dissolution profile when tested in a USP type 1 apparatus at 100 rpm in 900 mL of 0.3 M KCl-HCl buffer, pH 2.0 and at 37° C.: after 45 minutes not less than 95% of the angiotensin antagonist drug is released.
 60. A method for treating patients with circulatory system diseases, noninsulin-dependent diabetes mellitus or combinations of the forgoing comprising orally administering once-a-day to the patient an osmotic tablet comprising: (a) a core comprising: (i) 50-98% of an antihyperglycemic drug which is metformin or a pharmaceutically acceptable salt thereof; (ii) 0.1-40% of a binding agent; (iii) 0-20% of an absorption enhancer; and (iv) 0-5% of a lubricant; (b) optionally a seal coat surrounding the core; and (c) a sustained release membrane comprising: (i) 50-99% of a polymer; (ii) 0-40% of a flux enhancer; and (iii) 0-25% of a plasticizer, said membrane having at least one passageway formed therein for release of the antihyperglycemic drug; and (d) an angiotensin antagonist which is selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan, tasosartan, and telmisartan or pharmaceutically acceptable salts, isomers or derivatives thereof; and wherein said dosage form exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 mL of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37° C.: after 0.5 hours not less than 75% of the angiotensin antagonist drug is released; after 2 hours 0-25% of the antihyperglycemic drug is released; after 4 hours 10-45% of the antihyperglycemic drug is released; after 8 hours 30-90% of the antihyperglycemic drug is released; after 12 hours not less than 50% of the antihyperglycemic drug is released; after 16 hours not less than 60% of the antihyperglycemic drug is released; and after 20 hours not less than 70% of the antihyperglycemic drug is released.
 61. The method of claim 60, wherein said angiotensin antagonist is candesartan.
 62. The method of claim 50, wherein said dosage form is substantially free from any gelling or expanding polymer.
 63. The method of claim 60 wherein said release of said antihyperglycemic drug provides a T_(max) of 8-12 hours.
 64. The method of claim 60 wherein said release of the angiotensin antagonist provides a T_(max) of 1-12 hours.
 65. The method of claim 60 wherein said release of the angiotensin antagonist provides a T_(max) of 1-4 hours.
 66. The method of claim 60, wherein said dosage form exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 mL of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37° C.: after 2 hours 0-15% of the antihyperglycemic drug is released; after 4 hours 20-40% of the antihyperglycemic drug is released; after 8 hours 45-90% of the antihyperglycemic drug is released; after 12 hours not less than 60% of the antihyperglycemic drug is released; after 16 hours not less than 70% of the antihyperglycemic drug is released; and after 20 hours not less than 80% of the antihyperglycemic drug is released.
 67. The method of claim 60, wherein said dosage form exhibits the following dissolution profile when tested in a USP type 1 apparatus at 100 rpm in 900 mL of 0.3 M KCl-HCl buffer, pH 2.0 and at 37° C.: after 45 minutes not less than 85% of the angiotensin antagonist drug is released.
 68. The method of claim 60, wherein said dosage form exhibits the following dissolution profile when tested in a USP type 1 apparatus at 100 rpm in 900 mL of 0.3 M KCl-HCl buffer, pH 2.0 and at 37° C.: after 45 minutes not less than 90% of the angiotensin antagonist drug is released.
 69. The method of claim 60, wherein said dosage form exhibits the following dissolution profile when tested in a USP type 1 apparatus at 100 rpm in 900 mL of 0.3 M KCl-HCl buffer, pH 2.0 and at 37° C.: after 45 minutes not less than 95% of the angiotensin antagonist drug is released.
 70. A method for treating patients with circulatory system diseases, noninsulin-dependent diabetes mellitus or combinations of the forgoing comprising orally administering once-a-day to the patient an osmotic tablet, wherein the osmotic tablet comprises: (a) a core comprising: (i) 50-98% of an antihyperglycemic drug which is metformin or a pharmaceutically acceptable salt thereof; (ii) 0.1-40% of a binding agent; (iii) 0-20% of an absorption enhancer; (iv) 0-5% of a lubricant; and (v) an angiotensin antagonist which is selected from the group consisting of valsartan, losartan, candesartan, eprosartan, irbesartan, olmesartan, tasosartan, and telmisartan or pharmaceutically acceptable salts, isomers or derivatives thereof; (b) optionally a seal coat surrounding the core; and (c) a sustained release membrane comprising: (i) 50-99% of a polymer; (ii) 0-40% of a flux enhancer; and (iii) 0-25% of a plasticizer, said membrane having at least one passageway formed therein for release of the antihyperglycemic drug; and wherein said dosage form exhibits the following dissolution profile when tested in a USP type 2 apparatus at 75 rpm in 900 mL of simulated intestinal fluid (pH 7.5 phosphate buffer) and at 37° C.: after 0.5 hours not less than 75% of the angiotensin antagonist drug is released; after 2 hours 0-25% of the antihyperglycemic drug is released; after 4 hours 10-45% of the antihyperglycemic drug is released; after 8 hours 30-90% of the antihyperglycemic drug is released; after 12 hours not less than 50% of the antihyperglycemic drug is released; after 16 hours not less than 60% of the antihyperglycemic drug is released; and after 20 hours not less than 70% of the antihyperglycemic drug is released.
 71. The method of claim 70 wherein said core is substantially free from any gelling or expanding polymer.
 72. The method of claim 70 wherein said release of said antihyperglycemic drug provides a T_(max) of 8-12 hours.
 73. The method of claim 76 wherein said release of the angiotensin antagonist provides a T_(max) of 1-12 hours. 